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Pharmaco-Therapeutic Strategies When a Patient Fails to Respond to an Antidepressant

There are a number of options when a depressed patient does not respond to an antidepressant medication. These include:

  • Continuing the antidepressant at same dosage
  • Adjusting the dosage
  • Switching antidepressant, either to another within the same class or to one from a different class
  • Augmenting the antidepressant. The traditional augmentation agents are lithium (which is not indicated for the treatment of major depressive disorder in Australia), tri-iodothyronine* (T3, similarly not indicated r in Australia) and antipsychotics – particularly aripiprazole and quetiapine. About 30 to 50% of patients respond.
  • Combining antidepressants
  • Using physical treatments
  • Adding a nutraceutical, defined as any substance which is considered a food, a part of a food, a vitamin, a mineral, or a herb that provides health benefits. The table below outlines the options.

Table. Major nutraceuticals studied as augmentors in the pharmacologic treatment of depression

Folic acid Folate deficiency has been found in approximately one-third of people with depressive disorders and in poor responders to antidepressants.

Folate is involved in the methylation pathway in the “one C cycle” and responsible for metabolism and synthesis of serotonin and catecholamines.

Folate is also involved with synthesis of SAMe from homocysteine.

A Cochrane review concluded that folate may have a potential role as a supplement to other treatment for depression, although it is not clear if this is the case both for patients with normal and low folate levels.

Inositol Three studies using inositol as an augmenting agent with SSRIs demonstrated no significant difference between adjuvant use of inositol and placebo.
Lithium A study of the relationship between local lithium levels in drinking water in different regions of Austria and suicide mortality found that the overall suicide rate and suicide mortality ratio was significantly inversely associated with lithium levels.
L-tryptophan L-tryptophan is an essential amino acid precursor for synthesis of serotonin.

Many studies have small sample sizes and poor outcome measures. However, eight controlled augmentation studies using L-tryptophan with antidepressants provide encouraging evidence: it improved the antidepressant response to phenelzine sulphate, clomipramine, tranylcypromine, and fluoxetine. However, other clinical studies using tricyclics discovered no additional benefit compared to placebo.

Currently there is insufficient data to inform clinical practice.

Magnesium Magnesium has been shown in animal models to have anxiolytic effects.

A study found an inverse relationship between magnesium consumption and depressive symptom levels.

It may enhance mood stabilisation via modulating calcium channel activity to improve membrane stability and assist in regulating neurotransmitter release.

N-acetyl cysteine (NAC) NAC is an antioxidant precursor to glutathione, the primary endogenous antioxidant. Glutathione is responsible for maintaining oxidative balance in cells.

NAC may improve mood by modulating glutamatergic, neurotropic, and inflammatory pathways.

One study found that NAC significantly reduced depression levels, with a strong effect size. The dosage was 400 mg bd titrated to 800–1200 mg bd.

Omega-3 fatty acids Omega-3 fatty acids may exert antidepressant activity via beneficial effects on neurotransmission. They may modulate reuptake degradation, synthesis, and receptor binding of the neurotransmitters noradrenaline, dopamine, and serotonin. Animal models have demonstrated that omega-3 fatty acids increase serotonin and dopamine concentrations in the frontal cortex.

Two meta-analyses which demonstrated a positive benefit over placebo.

Evidence supports EPA or higher EPA to DHA formulations over DHA alone.

However, the effect size appears to be decreasing as more studies are done of better methodological rigour.

They may have an especially beneficial role in co-morbid cardiovascular conditions or if diet is deficient.

S-adenosyl methionine (SAMe) SAMe is a methyl donor for methyl groups involved in metabolism and synthesis of neurotransmitters, including serotonin and catecholamines.

Several human clinical trials using SAMe in major depressive disorders have shown promising antidepressant effects.

St Johns wort A Cochrane Review concluded that Hypericum extracts:

a) are superior to placebo in patients with major depression;

b) are similarly effective as standard antidepressants;

c) have fewer side effects than standard antidepressants.

Zinc Serum zinc levels are low in treatment-resistant major depressives.

Serum zinc levels normalise with successful antidepressant treatment.

Zinc is a non-competitive NMDA receptor antagonist.

Zinc augments the efficacy of imipramine.

Source: Professor Isaac Schweitzer, Healthed General Practice Education Day, Sydney 2012

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